Epizyme : Corporate Presentation, Feb. 2020

February 24, 2020

NASDAQ: EPZM

FORWARD-LOOKING STATEMENTS

Any statements in this presentation about future expectations, plans and prospects for Epizyme, Inc. (the "Company") and other statements containing the words "anticipate," "believe," "estimate," "expect," "intend," "may," "plan," "predict," "project," "target," "potential," "will," "would," "could," "should," "continue," and similar expressions, constitute forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Actual results may differ materially from those indicated by such forward-looking statements as a result of various important factors, including: uncertainties inherent in the initiation of future clinical studies and in the availability and timing of data from ongoing clinical studies; whether interim results from a clinical trial such as the interim data referenced in this presentation will be predictive of the final results of the trial; whether results from preclinical studies or earlier clinical studies will be predictive of the results of future trials; whether results from clinical studies will warrant meetings with regulatory authorities or submissions for regulatory approval; whether the Company will be able to satisfy the pathways to regulatory approval that it has identified;

whether the Company's cash resources will be sufficient to fund the Company's foreseeable and unforeseeable operating expenses and capital expenditure requirements; other matters that could affect the availability or commercial potential of the Company's therapeutic candidates; and other factors discussed in the "Risk Factors" section of the Company's most recent Form 10-K filed with the Securities and Exchange Commission (the "SEC") in February 2020 and in the Company's other filings from time to time with the SEC. In addition, the forward-looking statements included in this presentation represent the Company's views as of the date hereof and should not be relied upon as representing the Company's views as of any date subsequent to the date hereof. The Company anticipates that subsequent events and developments will cause the Company's views to change. However, while the Company may elect to update these forward-looking statements at some point in the future, the Company specifically disclaims any obligation to do so.

2

Rewriting Treatments for People with Cancer and Other Serious Diseases

3

EPIZYME:

A FULLY INTEGRATED

COMMERCIAL ENTERPRISE

TM

1 S TF D A A P P R O V A L J A N . 2 0 2 0

a c c e l e r a t e d a p p r o v a l g r a n t e d f o r

e p i t h e l i o i d s a r c o m a ( E S )

2 N DP O T E N T I A L A P P R O V A L J U N E 2 0 2 0

s u p p l e m e n t a l N D A f o r f o l l i c u l a r l y m p h o m a ( F L ) a c c e p t e d f o r f i l i n g w i t h p r i o r i t y r e v i e w

M U L T I - B I L L I O N

D O L L A R

G L O B A L M A R K E T O P P O R T U N I T Y I N E S a n d F L

T A Z E M E T O S T A T	H I G H - V A L U E
L I F E - C Y C L E	R E S E A R C H
D E V E L O P M E N T	P I P E L I N E
E X E C U T I O N	A D V A N C I N G
U N D E R W A Y	T O W A R D C L I N I C

W E L L -

C A P I T A L I Z E D

R U N W A Y I N T O A T L E A S T 2 0 2 2

Full prescribing information is available at www.TAZVERIK.com	4

TAZVERIK VALUE PROPOSITION AND PLATFORM FOR FUTURE GROWTH

TM

ORAL, AT-HOME	DEMONSTRATED ACTIVITY IN	FAVORABLE SAFETY
SOLID TUMORS AND
ADMINISTRATION	AND TOLERABILITY
HEME MALIGNANCIES

THERAPEUTIC OPPORTUNITIES	POTENTIAL FOR EXTENDED	EFFICIENT COMMERCIAL
IN RANGE OF CANCERS
TREATMENT DURATION	INFRASTRUCTURE
AND COMBINATIONS

Not for promotional use	5

ACCELERATED APPROVAL GRANTED BY U.S. FDA

TM

INDICATION: TAZVERIK is indicated for the treatment of patients aged 16 years and older with metastatic or locally advanced epithelioid sarcoma who are not eligible for complete resection

RECOMMENDED DOSE: 800 mg orally twice daily

WARNINGS & PRECAUTIONS:

• Secondary malignancies: Across clinical trials of 668 adults who received TAZVERIK 800 mg twice daily, myelodysplastic syndrome or acute myeloid leukemia occurred in 0.6% of patients. One pediatric patient developedT-cell lymphoblastic lymphoma
• Embryo-fetaltoxicity

ADVERSE REACTIONS: Most common AR (>20%, any grade)1are pain, fatigue, nausea, decreased appetite, vomiting, constipation. Dose reduction due to AR in one (2%) patient. Treatment discontinuation due to AR in one (2%) patient.

No Black Box warnings or contraindications

First and only EZH2	First and only treatment	NCCN Guidelines®
inhibitor approved	specifically indicated for	recommends TAZVERIK as
by U.S. FDA	ES by U.S. FDA	category 2A treatment

	Important safety information and full prescribing information are available at www.TAZVERIK.com
Not for promotional use	1Adverse reactions in 62 patients with histologically confirmed, metastatic or locally advanced	6
epithelioid sarcoma who received 800 mg twice daily of TAZVERIK

THREE STRATEGIC IMPERATIVES TO

SUCCESSFUL COMMERCIALIZATION OF TAZVERIK

1POSITIVE FIRST EXPERIENCE

Best-in-class TAZVERIK commercial infrastructure designed to reach all appropriate ES patients and provide patients and prescribers a positive experience with the brand

2WIDE ADOPTION AMONG PHYSICIANS

Phase 2 data support single-agent treatment with TAZVERIK can result in meaningful, durable responses in difficult-to-treat population

3	SEAMLESS PATIENT ACCESS
Comprehensive patient support that enables rapid access to TAZVERIK,
	timely reimbursement and financial assistance for those who need it
	-Programs in place: quick start, bridge supply, co-pay and patient assistance

Not for promotional use	Full prescribing information is available at www.TAZVERIK.com	7

EARLY SUCCESS IN ES LAUNCH BY HIGH-PERFORMING ORGANIZATION

üEfficient field-based team

activated across the US	~60	NCCN Centers of Excellence
		and academic/clinical centers

üEpizymeNOW facilitating new	focused on sarcomas
TAZVERIK prescriptions

• Focused on physician adoption, payer coverage with no barriers to access, and
  time to prescription fill

~70%

of patients treated at targeted NCCN and other clinical centers

TAZVERIK made available across U.S. within one week from approval

Not for promotional use	8

TAZVERIK sNDA ACCEPTED FOR FILING AND GRANTED PRIORITY REVIEW BY FDA

• Accelerated approval submissionfor TAZVERIK for relapsed or refractory FL patients who have received at least two prior lines of systemic therapy
• Submissionaccepted by FDA as sNDA, with common modules cross-referenced to approved ES NDA
• Fast Track designationpreviously granted for FL regardless of EZH2 mutational status
• Submission based primarily onefficacy findings in FL cohortsin Phase 2 trial

JUNE 18, 2020

TARGET PDUFA ACTION DATE

1NDA submitted December 18, 2010; accepted by US FDA as supplemental NDA

9

FOLLICULAR LYMPHOMA: An Incurable Disease Today

~10,000-12,000 PATIENTS WITH

RELAPSED/REFRACTORY FL IN THE U.S.1

DIAGNOSIS	2ND-LINE TREATMENT
•~14,000 diagnoses	•>50% treated with
annually in U.S.2	CD20-based combo chemo4

1ST-LINE TREATMENT

• ~80% receive systemic therapy, primarilyrituximab-based combo chemo3

MEDIAN SURVIVAL OF 10 YEARS FROM DIAGNOSIS 5; MEDIAN OF 3-4 SYSTEMIC THERAPIES5,6(range of 2-126)

3RD-LINE TREATMENT +

• Combo chemo treatment, PI3 kinase inhibitors,off-label agents or clinical trials4

CURRENT TREATMENTS SHOW

LIMITED BENEFIT WITH

SIGNIFICANT TOXICITIES

INTOLERANT TO THERAPY

• No continued treatment, palliative care
• Mortality

1Internal estimates 2Freedman et al. American Journal ofHematology; Volume 87, Issue 10. 3Bodor C. et al. Blood. 2013; 3Kantar Health 2019 US Treatment	10
Architecture; 4Cerhan J. et al. Best Pract Res Clin Haematol. 2011; 5Gopal, AK N Engl J Med. 2014; 6Aliqopa® (copanlisib) and Zydelig® (idelalisib) package inserts.

STRONG RESPONSE RATE AMONG PATIENTS WITH EZH2 ACTIVATING MUTATIONS IN PHASE 2 TRIAL

		MT EZH2 (n=45)
Endpoint n (%)
Investigator	IRC
ORR [CR+PR]	35	(78)	31	(69)
95% CIa	62.9-88.8	53.4-81.8
Complete Response (CR)	4	(9)	6 (13)
Partial Response (PR)	31	(69)	25	(56)
Stable Disease (SD)	10	(22)	13	(29)
DCR (CR+PR+SD) n (%)	43 (100%)
Progressive Disease		0	1	(2)

High concordance between IRC and investigator assessed response

% Change from Baseline in Sum of Products of Diameters

98%b(44 of 45) of patients with

evidence of tumor reduction by IRC

Data as of Aug 9, 2019; Morschhauser, F. Phase 2 Multicenter Study of Tazemetostat, an EZH2 Inhibitor, in Patients With Relapsed or Refractory Follicular Lymphoma, ASH 2019.

aBy Brookmeyer and Crowley method; bBest overall response based on Cheson (2007) criteria for lymphomas	11
CI, confidence interval; IRC, independent radiology committee; ORR, objective response rate; MT, mutant;

DURABLE RESPONSES OBSERVED IN PATIENTS WITH EZH2 ACTIVATING MUTATIONS IN PHASE 2 TRIAL

IRC Assessment

							MT EZH2
						Endpoint	Investigator	IRC
						Median time to first response,	3.8	3.7
						months (range)	(1.6-11.0)	(1.6-10.9)
(n=45)						Median duration of response,	8.3a	10.9a
					months (weeks), (95% CI)	(5.5, 13.8)	(7.2, NE)
					Median PFS, months,	13.8 (8.4, 16.4)	13.8 (10.7, 22.0)
Patients
					(95% CI)
			Enrolled in Rollover 501 Study	Patients ongoing, n (%)	13 (29)
				CR
				PR
				PD		8 (18%) patients continued
				Treatment ongoing
					treatment past progression
				PR to CR response
0	5	10	15	20	25	30

Months Since Treatment Initiation

Data as of Aug 9, 2019; Morschhauser, F. Phase 2 Multicenter Study of Tazemetostat, an EZH2 Inhibitor, in Patients With Relapsed or Refractory Follicular Lymphoma, ASH 2019.

aMedian DOR continues to mature for the MT EZH2 cohort.

12

MEANINGFUL RESPONSE RATE AMONG PATIENTS WITH WILD-TYPE EZH2 IN PHASE 2

							71%b(35 of 49) of patients with
		WT EZH2
					evidence of tumor reduction by IRC
		(n=54)
Endpoint n (%)
Investigator		IRC
							of
ORR [CR+PR]	18	(33)		19	(35)
			BaselinefromChangein Sum DiametersofProducts
95% CIa	21.1-47.5		22.7-49.4
Complete Response	3	(6)		2	(4)
(CR)
Partial Response (PR)	15	(28)		17	(31)
Stable Disease (SD)	16	(30)		18	(33)
DCR (CR+PR+SD) n (%)
						%
Progressive Disease	16	(30)		12	(22)

High concordance between IRC and investigator assessed response

Data as of Aug 9, 2019; Morschhauser, F. Phase 2 Multicenter Study of Tazemetostat, an EZH2 Inhibitor, in Patients With Relapsed or Refractory Follicular Lymphoma, ASH 2019.

aBy Brookmeyer and Crowley method. bBest overall response based on Cheson (2007) criteria for lymphomas. 13CI, confidence interval; IRC, independent radiology committee; ORR, objective response rate; WT, wild-type

COMPELLING DURABILITY AMONG

PATIENTS WITH WILD-TYPE EZH2 IN PHASE 2

							WT EZH2
						Endpoint	Investigator	IRCa
						Median time to first response,	3.5	3.7
						months (range)	(1.6- 16.3)	(1.6-16.3)
(n=54)						Median PFS,	5.6 (3.3, 11.1)	11.1 (3.7, 14.6)
					months (weeks), (95% CI)
Patients						Median duration of response	14.7	13.0
					((DOR (95%CI)), months	(7.6, NR)	(5.6-NR)
				Enrolled in Rollover 501 Study	Patients ongoing, n (%)		0 (0)
				CR
				PR		9 (17%) patients continued
				PD		treatment past progression
				Clinical progression
				Death without PD
				PR to CR response
0	5	10	15	20	25	30
		Months Since Treatment Initiation

Data as of Aug 9, 2019; Morschhauser, F. Phase 2 Multicenter Study of Tazemetostat, an EZH2 Inhibitor, in Patients With Relapsed or Refractory Follicular Lymphoma, ASH 2019.

aOf 19 patients who had an objective response, 10 (53%) had a response ≥ 6 months, 7(37%)	14
had a response ≥ 12 months, and 4(21%) had a response ≥ 18 months

MEDIAN OVERALL SURVIVAL NOT YET REACHED FOR MT AND WT EZH2 COHORTS IN PHASE 2

MT EZH2

WT EZH2

Endpoint	MT EZH2	WT EZH2
(n=45)	(n=54)
Median OS, months (95% CI)	NR (NE-NE)	NR (24.9-NE)
Median follow-upa, months (95% CI)	22.0 (16.6-24.6)	35.9 (32.2-39.0)

+, censored; CI, confidence interval; FL, follicular lymphoma; ITT, intent-to-treat; MT, mutant; NE, non-estimable;

Data as of Aug 9, 2019; Morschhauser, F. Phase 2 Multicenter Study of Tazemetostat, anaCalculated based on reverse Kaplan-Meier method15EZH2 Inhibitor, in Patients With Relapsed or RefractoryNR,Follicularnot reached;Lymphoma,OS,ASHoverall2019. survival.

FAVORABLE TOLERABILITY IN HEAVILY PRETREATED

PHASE 2 FL PATIENT POPULATION

TAZVERIK generally well tolerated in both cohorts

• 8% discontinued treatment due totreatment-related AE
• 9% dose reduced due totreatment-related AE
• 27% of patients had a dose interruption due to TEAEs
• Low rate of grade ≥3treatment-related TEAEs

No treatment-related deaths on study

	All Treatment-Emergent AEs	Treatment-related AEs
Category, n (%)	(TEAEs) (N=99)			(N=99)
	All Gradesa	Grade ≥3b	All Gradesa	Grade ≥3b
Nausea	23 (23)	0 (0)	19	(19)	0 (0)
Asthenia	19 (19)	3 (3)	15	(15)	1 (1)
Diarrhea	18 (18)	0 (0)	12	(12)	0 (0)
Fatigue	17 (17)	2 (2)	12	(12)	1 (1)
Alopecia	17 (17)	0 (0)	14	(14)	0 (0)
Cough	16 (16)	0 (0)	2	(2)	0 (0)
Upper respiratory tract infection	15 (15)	0 (0)	1	(1)	0 (0)
Bronchitis	15 (15)	0 (0)	3	(3)	0 (0)
Anemia	14 (14)	5 (5)	9	(9)	2 (2)
Abdominal pain	13(13)	1 (1)	2	(2)	0 (0)
Headache	12 (12)	0 (0)	5	(5)	0 (0)
Vomiting	12 (12)	1(1)	6	(6)	0 (0)
Back pain	11 (11)	0 (0)	0	(0)	0 (0)
Pyrexia	10 (10)	0 (0)	2	(2)	0 (0)
Thrombocytopenia	10 (10)	5 (5)	8	(8)	3 (3)

Data as of May 24, 2019: Morschhauser, F. Phase 2 Multicenter Study of Tazemetostat, an EZH2 Inhibitor, in Patients With Relapsed or Refractory Follicular Lymphoma, ASH 2019.

aAll grades TEAEs reported as occurring in ≥10% of patients;	16
bGrade ≥3 TEAEs reported in ≥ 5% patients.

GLOBAL CONFIRMATORY TRIAL UNDERWAY; DESIGNED TO SUPPORT TAZVERIK IN 2ND-LINE FL

PATIENT ENROLLMENT UNDERWAY; EXPECT TO COMPLETE SAFETY PORTION

AND BEGIN PHASE 3 EFFICACY PORTION IN 2020

DIAGNOSIS

• ~14,000 diagnoses annually in U.S.1

CURRENT TREATMENTS SHOW LIMITED

BENEFIT WITH SIGNIFICANT TOXICITIES

2ND-LINE TREATMENT

EXPANSION OPPORTUNITY

TAZVERIK + R2

Phase 1b/3 trial evaluating TAZVERIK + R2vs placebo + R2

in ~500 patients who received 1 or more prior systemic therapies

Designed to optimize potential for success

• TAZVERIK clinical activity demonstrated in R/R FL patients in Phase 2 trial1
• Preclinical synergy of TAVERIK with Revlimid2; clinical activity with R-CHOP3
• Maintenance therapy stage included to study continued treatment effect on PFS
• Adaptive design with interim assessments enables trial adjustment(s) based on TAZVERIK activity

R2= Revlimid®in combination with a rituxmab product is indicated for the treatment of adult patients with previously treated follicular lymphoma	17
1Morschhauser, F. Phase 2 Multicenter Study of Tazemetostat, an EZH2 Inhibitor, in Patients With Relapsed or Refractory Follicular Lymphoma, ASH 2019. 2Epizyme internal research

3Sarkozy, C. Results from a Phase Ib evaluation of tazemetostat (EPZ-6438) in combination with R- CHOP in poor prognosis newly diagnosed Diffuse Large B Cell Lymphoma (DLBCL): a LYSA Study, ASH 2018.

TAZVERIK DEVELOPMENT PROGRAM DESIGNED TO SUPPORT TREATMENT OF FL PATIENTS IN ALL LINES

~10,000-12,000 PATIENTS WITH RELAPSED/REFRACTORY FL IN THE U.S.

DIAGNOSIS

• ~14,000 diagnoses annually in U.S.1

CURRENT TREATMENTS SHOW

LIMITED

BENEFIT WITH SIGNIFICANT

TOXICITIES

1ST-LINE TREATMENT

2ND-LINE TREATMENT

3RD-LINE TREATMENT & BEYOND

EXPANSION OPPORTUNITY

EXPANSION OPPORTUNITY

EXPANSION OPPORTUNITY

TAZVERIK + R-CHOP

TAZVERIK + R2

TAZVERIK + rituximab

in high-risk FL patients

IST to begin in 2020

Confirmatory Phase 1b/3 trial

TAZVERIK + venetoclax

LYSA study to begin in 2020

currently enrolling patients

IST to begin in 2020

R2= Revlimid®in combination with a rituxmab product is indicated for the treatment of adult patients with previously treated follicular lymphoma	18
1Freedman et al. American Journal ofHematology; Volume 87, Issue 10.

EXPANSIVE TAZEMETOSTAT DEVELOPMENT PROGRAM

FOR NEW INDICATIONS AND COMBINATIONS

	THERAPEUTIC AREA	TREATMENT APPROACH
	Lymphomas & B-Cell Malignancies	Inhibit tumor proliferation
	governed by EZH2 expression
	Mutationally Defined Solid Tumors	Inhibit abnormal EZH2 function,
	restoring cells to natural state
TAZEMETOSTAT
LIFE-CYCLE
DEVELOPMENT	Chemo/Treatment-Resistant Tumors	Re-sensitize tumors to chemo
	and other therapies (e.g., PARP)
	I/O Sensitive Tumors	Re-sensitize tumors to
	immuno-oncology therapies

INDICATIONS OF INTEREST

• DLBCL
• CLL and CML
• Other lymphomas
• Chordoma
• Melanoma
• Tumors with SWI/SNF alteration
• Triple negative breast cancer
• Small cell lung cancer
• Ovarian cancer
• Mesothelioma
• Castration-resistantprostate cancer
• Colorectal cancer
• Bladder cancer
• Soft tissue sarcomas
• Non-smallcell lung cancer

4 ADDITIONAL STUDIES TO BEGIN IN 2020 THROUGH BOTH IN-HOUSE EFFORTS AND INVESTIGATOR-SPONSORED TRIALS AND ACADEMIC COLLABORATIONS

19

EARLY PIPELINE AND RESEARCH PLATFORM REPRESENTS SUBSTANTIAL UPSIDE VALUE

Multiple targets	Two HAT and helicase	Pinometostat	PRMT1 and PRMT5
identified for early	programs advancing	in development	inhibitor programs
discovery and	in research toward	for various leukemias2	advanced into clinical
research programs	named development		development3
	candidates1

1Boehringer Ingelheim and Epizyme will jointly research and develop a helicase program and share U.S. commercialization; BI holds ex-US commercialization rights; Boehringer	20
Ingelheim and Epizyme will jointly research a HAT program with BI holding global development and commercialization rights; 2Celgene holds ex-US rights to pinometostat;
development also being conducted under CRADA with National Cancer Institute 3GlaxoSmithKline holds global development and commercialization rights.

FINANCIALLY STRONG

Started 2020 with > $430M in cash and cash equivalents, inclusive of $50M put option exercised with Royalty Pharma in January

Significant funding agreements with Royalty Pharma and Pharmakon

• $150M in equity investments by Royalty Pharma1with potential for up to $50M in future equity option by Royalty Pharma2
• Reduced royalty obligation owed by Epizyme to Royalty Pharma on worldwide net sales of tazemetostat outside Japan3
• $70M expandable loan facility with Pharmakon Advisors to fund regulatory milestone payments to Eisai, once achieved4

2020 GAAP operating expenses anticipated to be between $300 - $330M with non-GAAP OPEX between $235 - $255M

1. Comprised of $100M upfront equity investment ad $50M put option exercised by Epizyme executed in January 2020
2. Royalty Pharma hasthree-year option to purchase additional 2.5M shares of Epizyme common stock at $20 per share
3. Royalty Pharma purchased future royalties on tazemetostat from Eisai for $110M upfront with rights to receive up to $220M in potential future milestones; Epizyme assigned to Royalty Pharma future royalty streams on tazemetostat sales
   in Japan previously owed to Epizyme by Eisai
4. $25M initial drawn down and remainder of facility may be drawn down in up to 2 additional tranches; facility expandable by up to $300M following approval of tazemetostat in follicular lymphoma, subject to mutual agreement

CASH RUNWAY INTO AT LEAST 2022

Capital to Support Commercialization in

ES and FL and Expansion of Tazemetostat Development

21

2020A TRANSFORMATIONAL YEAR

E P I T H E L I O I D S A R C O M A

• Gain FDA approval and launch tazemetostat in the U.S.

• Complete safety evaluation of tazemetostat in combination with doxorubicin and advance confirmatory trial infront-line ES

F O L L I C U L A R L Y M P H O M A

• Gain FDA approval and launch tazemetostat in the U.S.
• Complete safety evaluation of tazemetostat in combination with R2 and advance confirmatory trial insecond-line FL
• Initiate clinical investigation in combination withR-CHOP in front-line

T A Z E M E T O S T A T E X P A N S I O N

• Initiate Phase 2 portion of Phase 1b/2 trial in CRPC
• Initiate clinical trial in combination with PARP inhibitor
• Supportinvestigator-sponsored studies designed to demonstrate proof-of-concept in various combinations for multiple tumor types

R E S E A R C H

• Pursue additional development candidates for preclinical programs

P A R T N E R P I P E L I N E

•Advance partnered programs through key milestones	22

SUCCESSFULLY TRANSITIONED TO A COMMERCIAL ORGANIZATION

KEY 2020 PRIORITIES

SUCCESSFULLY LAUNCH

TAZVERIK IN U.S.

EXPAND TAZEMETOSTAT DEVELOPMENT

ENHANCE DEPTH OF PIPELINE

Commercialize TAZVERIK in U.S. for patients with epithelioid sarcoma and gain U.S. FDA approval for and launch in follicular lymphoma

Advance life-cycle development for tazemetostat to support future utility in additional indications and combinations

Progress preclinical efforts and pursue additional development candidates

23